Predictors of clinically significant prostate cancer in biopsy-naïve and prior negative biopsy men with a negative prostate MRI: improving MRI-based screening with a novel risk calculator

Purpose: A pre-biopsy decision aid is needed to counsel men with a clinical suspicion for clinically significant prostate cancer (csPCa), despite normal prostate magnetic resonance imaging (MRI). Methods: A risk calculator (RC) for csPCa (International Society of Urological Pathology grade group (ISUP) ⩾ 2) presence in men with a negative-MRI (Prostate Imaging–Reporting and Data System (PI-RADS) ⩽ 2) was developed, and its performance was compared with RCs of the European Randomized Study of Screening for Prostate Cancer (ERSPC), Prostate Biopsy Collaborative Group (PBCG), and Prospective Loyola University mpMRI (PLUM). All biopsy-naïve and prior negative biopsy men with a negative-MRI followed by systematic prostate biopsy were included from October 2015 to September 2021. The RC was developed using multivariable logistic regression with the following parameters: age (years), family history of PCa (first- or second-degree family member), ancestry (African Caribbean/other), digital rectal exam (benign/malignant), MRI field strength (1.5/3.0 Tesla), prior negative biopsy status, and prostate-specific antigen (PSA) density (ng/ml/cc). Performance of RCs was compared using receiver operating characteristic (ROC) curve analysis. Results: A total of 232 men were included for analysis, of which 18.1% had csPCa. Parameters associated with csPCa were family history of PCa (p < 0.0001), African Caribbean ancestry (p = 0.005), PSA density (p = 0.002), prior negative biopsy (p = 0.06), and age at biopsy (p = 0.157). The area under the curve (AUC) of the developed RC was 0.76 (95% CI 0.68–0.85). This was significantly better than the RCs of the ERSPC (AUC: 0.59; p = 0.001) and PBCG (AUC: 0.60; p = 0.002), yet similar to PLUM (AUC: 0.69; p = 0.09). Conclusion: The developed RC (Prostate Biopsy Cohort Amsterdam (‘PROBA’ RC), integrated predictors for csPCa at prostate biopsy in negative-MRI men and outperformed other widely used RCs. These findings require external validation before introduction in daily practice.


Introduction
Diagnostic prostate magnetic resonance imaging (MRI) is well established as a diagnostic modality for men with a clinical suspicion for prostate cancer (PCa). Multiple (randomized) trials showed that performing a pre-biopsy prostate MRI increased the detection of clinically significant prostate cancer (csPCa). [1][2][3][4] Consequently, current international guidelines strongly recommend performing prostate MRI before biopsy. 5 Following a positive MRI (i.e. Prostate Imaging-Reporting and Data System (PI-RADS) classification of ⩾ 3), there is a clear indication for MRI-targeted biopsy that can be complemented with systematic biopsy (SBx). 6 However, following a negative-MRI (i.e. PI-RADS ⩽ 2), there is no clear consensus on whether prostate biopsy should be performed.
Omitting SBx following a negative-MRI has the advantage of reducing diagnosis of insignificant prostate cancer (iPCa) and related overtreatment and avoiding prostate biopsy-related patient burden and morbidity. 6 It also carries a risk of missing csPCa and related treatment delay, possibly leading to disease progression. 6 To assist in clinical decision making, multiple risk calculators (RCs) have been developed that are able to predict csPCa presence. RCs are based on data of large cohorts and use a combination of patient-specific characteristics (e.g. age, digital rectal examination (DRE), prostate volume, prostate-specific antigen (PSA) levels, previous prostate biopsy results, prostate MRI results) to estimate the risk of having PCa at biopsy. 7 RCs show significantly better predictive accuracy compared with individual variables, such as PSA alone. However, they suffer from limited generalizability and poor calibration with validation studies, often overestimating the risk for PCa. 7,8 Specifically in men with negative-MRI, more data are needed to address the question in which of these men SBx can be safely omitted. 9 Considering the aging population and shifting views on early detection, this topic will become more relevant. In the latest statement of the US Preventive Services Task Force, screening based on PSA for men aged 55-69 years is no longer discouraged. 10 More screening will inevitably lead to an increased number of (negative) prostate MRIs, highlighting the need for reliable predictive factors for men at risk of significant disease, despite a negative-MRI.
Therefore, the aim of this study was to develop a RC for the presence of csPCa at SBx in men with a negative-MRI using a wide set of clinical parameters, and second, to compare the performance of the RC with that of widely used RCs.

Patients and methods
In both participating centers, performing a prebiopsy MRI was regularly performed for men with a clinical suspicion of PCa. All biopsy patients were prospectively registered from October 2015 and September 2021. Biopsy naïve or prior negative men were included in this subgroup analysis if their prostate MRI was negative (PI-RADS 1-2) and performed within 6 months prior to prostate biopsy. Men with prior PCa treatment or prior positive prostate biopsies were excluded. The study was approved by the Institutional Review Board of the participating centers (reference number: W21_534). The Ethical Committee confirmed that The Medical Research Involving Human Subjects Act (in Dutch: WMO) does not apply for this registry. As the current study exclusively re-uses care data for the purpose of research, written patient consent was not required.

MRI scan and image interpretation
Pre-biopsy prostate MRI was conducted using a 1.5 Tesla AVANTO® MRI scanner (Siemens, Healthcare, Erlangen, Germany) or a 3 Tesla INGENIA® MRI scanner (Philips Medical Systems, Best, the Netherlands). MRI series consisted of at least T1-weighted, T2-weighted, diffusion-weighted imaging and calculation of apparent diffusion coefficient maps. All prostate MRIs were evaluated by dedicated uroradiologists (>5 years' experience) according to the PI-RADS classification version 2 or 2.1. 11,12 Biopsy procedure Systematic prostate biopsy (SBx) procedures were performed transrectally or transperineally by dedicated operators (>150 procedures/year), based on a modified Barzell template of the peripheral and transitional zone. 13 Biopsy cores were retrieved using an 18G biopsy gun, independently labeled and fixated in separate containers

Results
The database consisted of a total of 790 men, of which 232 men were eligible for analysis ( Figure  1). This cohort consisted of 188 biopsy-naïve (81%) and 44 prior negative biopsy men (19%). The overall median (interquartile range (IQR)) age was 64 (10) years. The median (IQR) prebiopsy PSA was 6.5 (4.1) ng/ml and median (IQR) prostate volume of 55 (34) cc. This resulted in a median (IQR) PSA density of 0.12 (0.09) ng/ ml/cc. A suspicious digital rectal exam was identified in 40 men (17.2%) and a family history of PCa was found in 29 men (12.5%). Table 1 provides an overview of all patient characteristics.

Performance of 'PROBA RC' compared with other RC
Systematic prostate biopsy detection rates of PCa and csPCa were 36.6% (85 men) and 17.2% (40 men), respectively. ISUP ⩾ 3 was detected in 11 men (4.7%). Multivariable logistic regression analysis showed that a family history of PCa (p < 0.0001), African Caribbean ancestry (p = 0.005), PSA density (p = 0.002), prior negative biopsy (p = 0.063), and age at biopsy (p = 0.157) were associated with csPCa presence (Table 2), and, therefore, included in the final 'PROBA RC'. The AUC of the 'PROBA RC' 0.76 (95% CI 0.68 -0.85) was higher than the AUC of the RCs of the ERSPC (p = 0.001), PBCG (p = 0.002) and PLUM (p = 0.09), which  of 0.76. 17 The PLUM RC includes age, PSA, DRE, prostate volume, ancestry, family history of PCa, prior negative biopsy, and MRI results, which resulted in an AUC of 0.88 for biopsy naïve and 0.87 for prior negative biopsy men. This seems a promising RC, yet it has not been externally validated.
Where the 'PROBA', PBCG, and PLUM RCs include ancestry and family history, the ERSPC RC does not. The role of ancestry for the prediction of csPCa remains controversial, yet it is suggested by the European guidelines as a potential risk factor. 5 In a recent meta-analysis on predictive factors for csPCa in negative-MRI men, ancestry was investigated in one study, and it was not found to be a significant predictor. 9 However, epidemiological studies have shown a higher prevalence of PCa in populations of African descent (OR 3.34). 18 In the present study, an association between African Caribbean ancestry and csPCa was confirmed (p = 0.005).
Family history has also shown to be related to csPCa with incidence ratios of up to 4.0 for first degree relatives in population-based studies. [19][20][21] In our study, family history for PCa was the predictor with the largest association with csPCa, with an OR of 8.42. The fact that this factor is not included in the ERSPC RC might explain the underperformance compared with the 'PROBA' and PLUM RCs. The PBCG RC still performed similarly to the ERSPC RC, possibly because it does not include MRI results.
In all investigated RCs, PSA and prostate volume are included. In the current cohort, a higher PSA density was significantly related to the presence of csPCa. In the recent meta-analysis by Pagniez et al., 9 PSA density was the most relevant predictive factor of csPCa presence in biopsy-naïve and prior negative biopsy men. They showed that the NPV of a negative-MRI for csPCa presence improved, when selecting a PSA density cut-off of < 0.15 ng/ml/cc, in both biopsy-naïve (82.7-88.7%) and prior negative biopsy men (88.2-94.1%).
Furthermore, in this meta-analysis, two studies were included assessing the predictive value of a prior negative biopsy status. Both studies found that a prior negative biopsy status was significantly associated with the absence of csPCa, with an OR up to 5.2 (95% CI 1.6-16.5; p = 0.005). In the present study, similar results were found regarding the prior negative biopsy status.
To our knowledge, this is the first study assessing predictors for the presence of csPCa in men with a negative-MRI. Whether to implement a novel RC in regular practice depends mainly on the clinical implications of applying the RC. By only performing SBx in men with an 'PROBA RC': ⩾ 20%, 163 out of 232 (70.3%) men could have prevented SBx, leading to a reduction of 37 (15.9%) iPCa cases detected at the cost of 13 (5.6%) missed csPCa cases. Interestingly, none of the missed csPCa cases showed high-risk characteristics, all being ISUP ⩽ 3, without cribriform growth and a low number of positive biopsy cores. Five out of these 13 (38.5%) men with missed csPCa did not receive active treatment, considering they were eligible for active surveillance. 22 Therefore, arguably, only 7 clinically relevant PCa cases out of 232 (3%) SBx patients were missed. We conclude that SBx can be safely omitted in selected men with a negative-MRI and a risk of < 20% for the 'PROBA RC'.
This study has several limitations. Although the 'PROBA RC' showed promising results for men with a negative-MRI, it requires external validation to evaluate its applicability in general practice. Besides, diagnostic accuracy of both MRI and prostate biopsy is dependent on locally available expertise of radiologists and biopsy operators. [23][24][25] Consequently, the applicability of RCs will differ depending on the clinic. The discrepancy between the predictive values of our local 'PROBA RC' and other RCs highlights this issue and shows the importance of locally evaluating MRI and biopsy performance. Also, due to its retrospective design, this study is at risk for selection bias. Moreover, it is limited by a relatively small sample size. In addition, the reference standard was SBx and not template biopsies, which might underestimate the presence of csPCa. Furthermore, performance of the 'PROBA RC' could be further increased by incorporating other risk factors, for example, family history of BRCA2 mutation, hereditary breast and ovarian cancer, and Lynch syndrome. 26,27 Whether to perform SBx in men with a negative-MRI remains a topic of discussion. The longterm clinical implication of omitting SBx is an important factor in this discussion. No high-level, prospective evidence is available to support omitting SBx in all men with a negative-MRI. Currently, the decision to proceed with SBx after a negative-MRI should be based on patient-specific characteristics. The use of RCs can aid in clinical decision making, but the accuracy of these calculators might vary between centers. Local evaluation of biopsy and prostate MRI results is paramount to guarantee the best quality of care for each patient.

Conclusion
Shared decision making for performing SBx in men with a negative prostate MRI can be improved based on family history of PCa, African Caribbean ancestry, PSA density, prior negative biopsy status, and age at biopsy. The 'PROBA RC', developed in the present study integrating these predictors, performed superior when compared with widely available RCs. These findings require external validation before introduction in daily practice.